Article

Clinical variability of Stickler syndrome with a COL2A1 haploinsufficiency mutation: implications for genetic counselling.

Journal of Medical Genetics (Impact Factor: 5.7). 05/2000; 37(4):318-20. DOI: 10.1136/jmg.37.4.318
Source: PubMed
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    ABSTRACT: Mutations in COL2A1, the gene for type II-collagen, can result in a wide variety of phenotypes depending upon the nature of the mutation. Dominant negative mutations tend to result in severe and often lethal skeletal dysplasias such as achondrogenesis type 2, Kniest dysplasia, and spondyloepiphyseal dysplasia congenita. Stickler syndrome, a condition characterized by ophthalmological and orofacial features, deafness and arthritis, usually, but not exclusively, results from haploinsufficiency. Overlapping features of all these disorders can also be seen in the same family. Rare reports have demonstrated that phenotypic variability can be explained in some families by somatic mosaicism. Here, we describe five further examples of somatic mosaicism of COL2A1 mutations illustrating the importance of detailed clinical evaluation and molecular testing even in clinically normal parents of affected individuals.
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    ABSTRACT: The ocular findings, systemic features, and genetic loci distinguishing known genetic causes of vitreoretinal degenerations were studied in the original Snowflake family. Prospective, comparative study and molecular genetic investigation. Members of the original snowflake vitreoretinal degeneration family. Clinical data were collected on 26 family members by history and examination. Thirteen of the 26 total family members underwent prospective examination. Linkage to known vitreoretinal degeneration loci (COL2A1, COL11A1, and the Wagner disease locus) was evaluated with short tandem repeat markers. Ocular and systemic features of known vitreoretinal degenerations. Six of the 13 prospectively examined subjects had snowflake vitreoretinal degeneration. Corneal guttae (4/5; 80%), early onset cataract (5/6; 83%), fibrillar vitreous degeneration (6/6; 100%), and peripheral retinal abnormalities (5/6; 83%), including minute crystallinelike deposits called snowflakes (4/6; 67%), were common. Retinal detachment was seen in 1 of 6 of these prospectively examined subjects (17%). A total of 14 affected subjects were identified within the family, and in 3 (21%), retinal detachment developed. Orofacial features, early-onset hearing loss, and arthritis typical of Stickler syndrome were absent. Linkage to known vitreoretinal degeneration loci was excluded. The absence of vitreous gel in the retrolental space and presence of fibrillar vitreous degeneration were consistent with the vitreous structure reported for collagen 11A1 (COL11A1) but not collagen 2A1 (COL2A1) mutations. The absence of systemic features was characteristic of the vitreoretinopathies linked to chromosome 5q13 (Wagner disease and erosive vitreoretinopathy) and mutations in exon 2 of the COL2A1 gene. Snowflakes in the peripheral retina and the absence of nyctalopia, posterior chorioretinal atrophy, and tractional retinal detachment were inconsistent with the chromosome 5q13 vitreoretinopathies. The association of Fuchs' corneal endothelial dystrophy found in this family has not been reported previously in other vitreoretinal degenerations. These findings and the exclusion of known genetic loci suggest snowflake is a distinct vitreoretinal degeneration.
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